HLD-NAC design and evaluation of a fully dilutable lecithin-linker SMEDDS for ibuprofen.

Lecithin-linker microemulsions have been previously proposed as a platform for designing a fully dilutable self-microemulsifying drug delivery system (SMEDDS). This SMEDDS formulation, composed of ethyl caprate (oil), lecithin (Le), glycerol monooleate (lipophilic linker, LL) and polyglycerol caprylate (hydrophilic linker, HL), produced a ternary phase diagram (TPD) that had a fully dilutable path suitable for oral drug delivery. However, introducing ibuprofen as an active pharmaceutical ingredient (API) resulted in TPD phase boundaries that eliminated the fully dilutable path. The purpose of this work was to understand the origin of the changes in the TPD, use that understanding to restore the fully dilutable path with an ibuprofen-loaded SMEDDS, and finally to evaluate the absorption of ibuprofen in vivo. The effect of ibuprofen on the HLD (hydrophilic-lipophilic difference, interpreted as normalized net interfacial curvature) of the system was evaluated via a polar oil model, showing that ibuprofen played a surfactant-like role, having a characteristic curvature (Cc) value of +5 (highly hydrophobic). The net-average curvature (NAC) framework used the HLD calculated with Le, LL, HL and ibuprofen Cc to generate TPDs in ibuprofen lecithin-linker systems. The HLD-NAC simulations show that restoring full dilutability required a highly hydrophilic linker (HL-) with a Cc of -5 or more negative. The fully dilutable path was restored after introducing a hexaglycerol caprylate as HL- (Cc = -6). Plasma concentration profiles obtained with this ibuprofen-loaded SMEDDS showed a more than three-fold increase in the area under the curve (AUC) of rat plasma concentration profiles compared to the same 25 mg/kg ibuprofen dose in suspension.

Inter- and intra-observer variability of the Los Angeles classification: a reassessment.

BACKGROUND: Los Angeles classification is widely adopted for reporting endoscopic gastroesophageal reflux disease. We assessed the inter- and intra-observer variability of the Los Angeles classification. METHODS: Still images (n = 254) of the lower esophagus were presented to 9 gastroenterologists (6 experts and 3 trainees) and they were asked to report the images according to the Los Angeles classification. After 2 weeks the images were reordered and they were asked to report them again. Kappa statistic was calculated for intra- and inter-observer variability. RESULTS: The kappa for intra-observer agreement was 0.54 (attendings: 0.54; trainees; 0.55; P = not significant) and the inter-observer agreement was 0.22 (attendings: 0.20; trainees: 0.31; P = 0.027). The inter- and intra-observer kappa values in differentiating nonerosive from erosive cases were 0.22 (attendings: 0.21; trainees: 0.31, P = not significant) and 0.57 (attendings: 0.58; trainees: 0.55, P = not significant), respectively. CONCLUSION: According to our data, the Los Angeles classification has acceptable intra-observer variability, both for detecting presence or absence of erosions and for differentiating between different degrees of esophagitis, while its inter-observer performance seems to be less acceptable. It may be reasonable and timely to have another look at the Los Angeles classification to see whether its performance can be improved even further.

Predicting solubilisation features of ternary phase diagrams of fully dilutable lecithin linker microemulsions.

Fully dilutable microemulsions (µEs), used to design self-microemulsifying delivery system (SMEDS), are formulated as concentrate solutions containing oil and surfactants, without water. As water is added to dilute these systems, various µEs are produced (water-swollen reverse micelles, bicontinuous systems, and oil-swollen micelles), without the onset of phase separation. Currently, the formulation dilutable µEs follows a trial and error approach that has had a limited success. The objective of this work is to introduce the use of the hydrophilic-lipophilic-difference (HLD) and net-average-curvature (NAC) frameworks to predict the solubilisation features of ternary phase diagrams of lecithin-linker µEs and the use of these predictions to guide the formulation of dilutable µEs. To this end, the characteristic curvatures (Cc) of soybean lecithin (surfactant), glycerol monooleate (lipophilic linker) and polyglycerol caprylate (hydrophilic linker) and the equivalent alkane carbon number (EACN) of ethyl caprate (oil) were obtained via phase scans with reference surfactant-oil systems. These parameters were then used to calculate the HLD of lecithin-linkers-ethyl caprate microemulsions. The calculated HLDs were able to predict the phase transitions observed in the phase scans. The NAC was then used to fit and predict phase volumes obtained from salinity phase scans, and to predict the solubilisation features of ternary phase diagrams of the lecithin-linker formulations. The HLD-NAC predictions were reasonably accurate, and indicated that the largest region for dilutable µEs was obtained with slightly negative HLD values. The NAC framework also predicted, and explained, the changes in microemulsion properties along dilution lines.

Obesity and hypertension in an Iranian cohort study; Iranian women experience higher rates of obesity and hypertension than American women.

BACKGROUND: Once considered as the main public health problem in developed countries, obesity has become a major problem throughout the world and developing countries, like Iran, are joining the global obesity pandemic. We determined the prevalence of overweight, obesity, and hypertension in a large cohort of Iranians and compared age-adjusted rates with the rates in the US. METHODS: Golestan Cohort Study is a population-based study of 8,998 men and women, aged 35-81 years, from urban and rural areas. Anthropometric parameters were measured by interviewers. Prevalence rates were directly adjusted to the 2000 United States standard population. RESULTS: The age-adjusted prevalence rates of overweight (BMI > or = 25 kg/m2) and obesity (BMI > or = 30 kg/m2) in this Iranian population were 62.2% and 28.0%, respectively. Both overweight and obesity were more common in women than men. Age-adjusted prevalence of overweight was significantly higher in Iranian women compared to the American women (68.6% vs. 61.6%), while the age-adjusted prevalence of obesity is closer in these two populations (34.9% vs. 33.2%). Iranian men-compared to American men-had significantly lower age-adjusted prevalence of overweight (53.7% vs. 68.8%) and obesity (16.2% vs. 27.5%). Age-adjusted prevalence of hypertension was higher in Iranian women than American women (35.7% vs. 30.5%). Diabetes mellitus was reported in 6.2% of participants. Mean waist-to-hip ratio (WHR) among women was 0.96. Smoking rates in men and women were 33.2% and 2.2%, respectively. CONCLUSION: The prevalence of obesity, overweight, and hypertension in Iran is as high as the US. However, Iranian women are more obese than American women and Iranian men are less obese than their American counterparts. This discrepancy might be due to the low rate of smoking among Iranian women. Iranian women have higher mean WHR than what WHO has defined in 19 other populations.

Lecithin-linker formulations for self-emulsifying delivery of nutraceuticals.

Lecithin-linker microemulsions are formulations produced with soybean lecithin in combination with a highly lipophilic (lipophilic linker) and highly hydrophilic (hydrophilic linkers) surfactant-like additives. In this work, lecithin-linker systems were formulated to produce self-emulsifying delivery systems for ß-carotene and ß-sitosterol. The concentration of the lipophilic linker, sorbitan monooleate, was adjusted to minimize the formation of liquid crystals. The concentration of hydrophilic linkers, decaglyceryl caprylate/caprate and PEG-6-caprylic/capric glycerides, was gradually increased (scanned) until single phase clear microemulsions were obtained. For these scans, the oil (ethyl caprate) to water ratio was set to 1. The single phase, clear microemulsions were diluted with fed-state simulated intestinal fluid (FeSSIF) and produced stable emulsions, with drop sizes close to 200 nm. Using pseudo-ternary phase diagrams to evaluate the process of dilution of microemulsion preconcentrates (mixtures of oil, lecithin and linkers with little or no water) with FeSSIF, it was determined that self-emulsifying systems are obtained when the early stages of the dilution produce single phase microemulsions. If liquid crystals or multiple phase systems are obtained during those early stages, then the emulsification yields unstable emulsions with large drop sizes. An in vitro permeability study conducted using a Flow-Thru Dialyzer revealed that stable emulsions with drop sizes of 150-300 nm produce large and irreversible permeation of ß-carotene to sheep intestine. On the other hand, unstable emulsions produced without the linker combination separated in the dialyzer chamber.

Crohn's disease and early exposure to domestic refrigeration.

BACKGROUND: Environmental risk factors playing a causative role in Crohn's Disease (CD) remain largely unknown. Recently, it has been suggested that refrigerated food could be involved in disease development. We thus conducted a pilot case control study to explore the association of CD with the exposure to domestic refrigeration in childhood. METHODOLOGY/PRINCIPAL FINDINGS: Using a standard questionnaire we interviewed 199 CD cases and 207 age-matched patients with irritable bowel syndrome (IBS) as controls. Cases and controls were followed by the same gastroenterologists of tertiary referral clinics in Tehran, Iran. The questionnaire focused on the date of the first acquisition of home refrigerator and freezer. Data were analysed by a multivariate logistic model. The current age was in average 34 years in CD cases and the percentage of females in the case and control groups were respectively 48.3% and 63.7%. Patients were exposed earlier than controls to the refrigerator (X2 = 9.9, df = 3, P = 0.04) and refrigerator exposure at birth was found to be a risk factor for CD (OR = 2.08 (95% CI: 1.01-4.29), P = 0.05). Comparable results were obtained looking for the exposure to freezer at home. Finally, among the other recorded items reflecting the hygiene and comfort at home, we also found personal television, car and washing machine associated with CD. CONCLUSION: This study supports the opinion that CD is associated with exposure to domestic refrigeration, among other household factors, during childhood.